Water-insoluble cyclodextrin polymers and processes for their preparation

ABSTRACT

A hydrophilic, water-dilatable cyclodextrin polymerizate has a high cyclodextrin content which possesses good mechanical properties. The cyclodextrin pearl polymerizates are produced by radical, inversion suspension polymerization of cyclodextrin derivatives carrying methacrylate groups or their copolymerization with suitable comonomers such as hydroxyethylacrylate or hydroxymethylacrylate. Suitable cyclodextrin derivatives can be produced by reacting cyclodextrins or hydroxyalkyl cyclodextrins with methacrylic anhydride or with glycidyl methacrylate. The cyclodextrin polymerizates produced in this manner have mechanical properties appreciably superior to those of known, comparable cyclodextrin polymers.

The invention relates to water-insoluble cyclodextrin bead polymers,which are formed by free radical polymerization of cyclodextrinderivatives containing polymerizable groups, and to processes for theirpreparation.

Cyclodextrins are cyclic, non-reducing oligosaccharides, consisting ofα-D-glucose units which have exclusively 1,4-glucoside links. Currentlyα-, β- and γ-cyclodextrin, which are built up from 6, 7 and 8anhydroglucose units respectively, are available in relatively largeamounts. The most interesting property of the cyclodextrins is theirability to form inclusion complexes (host/guest compounds). In thesecompounds hydrophobic guest molecules of suitable size are enclosed inthe cyclodextrin cavity and reversibly bonded by hydrophobicinteractions, van der Waals forces and, in some cases, also hydrogenbridge bonds. By far the majority of applications of cyclodextrins arealso based on the formation of these inclusion complexes. Thus, forexample, they are suitable for chromatographic separations, ascatalysts, as stabilizers, for solubilization or for converting liquidsubstances into the solid aggregate state.

Since, because of their chiral C atoms, cyclodextrins are able to act asenantion-selective receptors, chromatographic separations of suitableenantiomers are also possible with the participation of cyclodextrininclusion compounds. As a result of these selective receptorcharacteristics, the stereoselectivity of chemical reactions can also beincreased by cyclodextrins. However, if dissolved cyclodextrin is usedas separating agent or extractant or as a catalyst, the separation ofthe inclusion compound from the system and the liberation of theincluded compound from the cyclodextrin are difficult. Therefore, animmobilization of cyclodextrins with the production of their inclusioncapacity is advantageous. Immobilized cyclodextrins can be used, forexample, as the stationary phase in separation processes inchromatography. Hitherto, an immobilization of cyclodextrins has beenattempted in very diverse ways. However, all previously describedimmobilization methods have defects.

Insoluble (immobilized) cyclodextrins and their use in separationprocesses have already been described by Solms and Egli (Helv. Chim.Acta 48, 1225 (1965)). In German Patent Specification DE 29 27 733, J.Szejtli et al. describe cyclodextrin-polyvinyl alcohol polymers and aprocess for their preparation. Compared with the cyclodextrin gels knownhitherto, these have somewhat better mechanical properties.

In J. Food Sci. 48, 646, (1983), P. E. Shaw and C. W. Wilson describethe use of such cyclodextrin polymers for separating bitter substancesfrom citrus juices.

In Gordian 89 (3), 43 (1989) A. Ujhazy and J. Szejtli also describe theseparation of a bitter substance (naringin) from aqueous solutions withthe aid of a cyclodextrin bead polymer.

In the case of the already known cyclodextrin gels which have beenmentioned, the immobilization of the cyclodextrins is achieved bybifunctional crosslinking agent units. A three-dimensional, hydrophiliccyclodextrin lattice which is swellable in water is formed. Material inbead form can be obtained by means of a method relating to inversesuspension polymerization. The crosslinking agent units used arepreferably epichlorohydrin or diepoxy compounds. However, all thecyclodextrin polymers prepared in this way which have been describedhitherto are unsuitable for filling columns which are operated under apressure distinctly higher which are operated under a pressuredistinctly higher than atmospheric pressure, since even under a pressureof 3 bar there is already a deformation of the packing such that theflow rates through a filled column are low. Moreover, when the pressureis increased, the flow-through rates do not increase substantiallybecause of the softness of the material. High flow-through rates are,however, desirable on economic grounds. Furthermore, an increase in theseparation efficiency can also be achieved by increasing the pressurefor a given column packing material.

In order to obtain a cyclodextrin-containing material which is suitableas column packing material for higher pressures, another process hasalso been proposed, in which, in contrast to the proposal alreadymentioned, cyclodextrin molecules are bonded directly or via a spacer toa pressure-stable parent polymer in bead form.

In U.S. Pat. No. 4,539,399 D. W. Armstrong describes the fixing ofcyclodextrins on silica gel as support material with the aid of linkingreagents such as, for example, 3-glycidoxypropyltrimethoxysilane. Thedecisive disadvantage of these materials is their low cyclodextrincontent. Thus, although these products are suitable for analyticalpurposes, they are, however, completely unsuitable for preparative usebecause of their low capacity.

In Japanese Patent Application 63 314 201 (CA 110 (1989): 175 437 q) theimmobilization of cyclodextrins by fixing on a copolymer which consistsof a glycidyl monovinyl ester (for example glycidyl methacrylate) or aglycidyl monovinyl ether (for example allyl glycidyl ether) and ethyleneglycol dimethacrylate is described. In this procedure the fixing of thecyclodextrins is effected by treatment of the copolymer with HCl, duringwhich treatment the epoxide rings of the glycidyl radical are opened,and subsequent reaction of this intermediate with a basic cyclodextrinsolution. However, materials prepared in this way have severaldisadvantages. In addition to their low cyclodextrin content, theimmobilization yield with respect to β-cyclodextrin is also low. Inaddition, the high content of relatively hydrophobic carrier polymer isa decisive disadvantage. This high proportion of hydrophobic sitesoutside the cyclodextrin cavities leads to unselective adsorptions ofhydrophobic substances from the solution to be treated. The result ofthis is that, on desorption or elution these, unselectively adsorbedsubstances are mixed with those which were selectively bound tocyclodextrin units.

In "Cyclodextrin Technology" (Kluwer Academic Publishers) 1988, p. 59 etseq., J. Szejtli gives a comprehensive review of the attempts describedhitherto for the immobilization of cyclodextrins. However, all of theseattempts to prepare materials which are swellable in water resulted inproducts which either have only a moderate mechanical stability or havea low cyclodextrin content. In some cases, the preparation process isadditionally so difficult and expensive that industrial utilizationappears to be precluded.

U.S. Pat. No. 3,565,887 relates to unsaturated esters of cyclodextrin.The possibility of polymerization of such compounds is only indicatedand the use as column packing material is not mentioned.

FR-A 2,334 691 describes dextran gels. In contrast to cyclodextrinderivatives, compounds of this type lack the capacity for inclusion in acavity.

EP-A 309,404 relates to copolymers of methacrylate with vinyl- oralkyl-substituted cyclodextrins and their use in pharmaceuticalformulations.

In Macromolecules 9, 701 (1976), von A. Harada, M. Furue and S. Nozakuradescribe the preparation of cyclodextrin acrylates and their freeradical polymerization to give soluble polymers. In this process thesynthesis of the polymerizable cyclodextrin derivatives was carried outby the Benders method by reaction of β-cyclodextrin with m-nitrophenylacrylate and subsequent chromatographic purification. Syntheses of thistype, which lead to monofunctional cyclodextrin derivatives, are,however, far too expensive for industrial purposes. Furthermore, onlysoluble products are described on polymerization thereof.

The object of the invention was to develop water-insoluble cyclodextrinpolymers which are simple to prepare and which, with a high cyclodextrincontent, at the same time possess improved mechanical propertiescompared with comparable polymers already known. The novel waterinsoluble polymers should also by hydrophilic and thus swellable inwater. In this context, the term "water-insoluble" is to be understoodto mean that, at room temperature, that is to say about 20° C., thepolymers are soluble in water to the extent of less than 0.1% by weight.

The invention relates to water-insoluble homopolymers or copolymers ofmethacrylate- or glyceryl methacrylate-substituted cyclodextrins, withthe exception of homopolymers of methacrylate-substituted cyclodextrins,or hydroxyalkylcyclodextrins, containing C₂ to C₄ hydroxyalkyl units, inparticular hydroxypropylcyclodextrins, the AS value of which is in eachcase between 0.3 and 0.9, and also copolymers of the abovementionedsubstituted cyclodextrins with water-soluble ethylenically unsaturatedcomonomers, from the group comprising acrylamide, 1-vinyl-2-pyrrolidone,hydroxyethyl acrylate and hydroxyethyl methacrylate. The above-notedexception refers only to homopolymers of methacrylate substitutedcyclodextrins.

In a particularly preferred embodiment, the cyclodextrin content in thesaid polymers is more than 30% by weight, preferably more than 40% byweight, based on the total polymer.

Suitable starting materials for the preparation of themethacrylate-substituted cyclodextrins or hydroxyalkyl cyclodextrins areα-, β- or γ-cyclodextrin and hydroxyalkylcyclodextrins containing C₂ toC₄ hydroxyalkyl units, in particular hydroxyethyl- andhydroxypropylcyclodextrins of α-, β- and γ-cyclodextrin. These areobtained in a known manner by reaction of the corresponding cyclodextrinwith an alkylene oxide, in particular with ethylene oxide or propyleneoxide, in a basic, aqueous medium. The product mixtures thus formed,consisting of a multiplicity of cyclodextrin units having differentsubstituents, are usually characterized with the aid of an MS value(degree of molar substitution). The MS value indicates how many alkyleneoxide molecules are bonded on average per anhydroglucose unit of acyclodextrin molecule. Since in the case of the reaction of thecyclodextrins with alkylene oxides in each case new OH groups areproduced in the substituent, which groups are, in turn, able to reactwith alkylene oxide molecules, in principle MS values higher than 3 arealso possible. The MS value can be determined with the aid of ¹ H NMRspectroscopy by simple comparison of the corresponding signal areas ofcyclodextrin signals and substituent signals. Hydroxyalkylcyclodextrinshaving MS values of 0.5-1.0 are particularly suitable for the beadpolymers according to the invention.

Cyclodextrin derivatives suitable for free radical polymerization areobtained by reaction of cyclodextrins (α, β or γ) andhydroxyalkylcyclodextrins with methacrylic anhydride in excess in basicorganic solvents at temperatures of 60°-100° C. Suitable solvents arepolar aprotic organic solvents, for example N,N-dimethylformamide,dimethyl sulfoxide or pyridine. Bases which can be used are amines, suchas, for example, triethylamine or pyridine. The cyclodextrinmethacrylates or hydroxyalkylcyclodextrin methacrylates formed duringthe reaction can be isolated by simple precipitation with liquidhydrocarbons, such as, for example, toluene, and subsequent filtration.Only simple washing with an aromatic hydrocarbon, such as, for example,toluene and n-propanol, is necessary as purification operation. Theresulting cyclodextrin methacrylates and hydroxyalkylcyclodextrinmethacrylates have a purity which is sufficient for free radicalpolymerization.

The cyclodextrin esters formed during the reaction with methacrylicanhydride also consist of molecules which are not of uniform structurebut consist of a multiplicity of cyclodextrin units having differentsubstituents. These substance mixtures, which are outstandingly suitablefor a polymerization, are characterized with the aid of an AS value(average degree of substitution). The AS value (determination analogousto the MS value by means of ¹ H NMR spectroscopy) indicates how manymethacrylate groups are present on average per anhydroglucose unit of acyclodextrin molecule. In principle, cyclodextrin methacrylates havingAS values of 0 to 3 can be prepared by the methods described. Since,however, readily water-soluble substances are required for thesubsequent polymerization to give hydrophilic insoluble bead polymers,only cyclodextrin methacrylates having AS values of between 0.3 and 0.9are suitable. Both products having a lower degree of substitution andthose having a higher degree of substitution in respect of themethacrylate groups have a solubility in water which is too low forinverse suspension bead polymerization. In addition, at least, onaverage, two methacrylate groups per cyclodextrin unit are required forthe preparation of crosslinked, insoluble polymers. Cyclodextrinmethacrylates and hydroxyalkylcyclodextrin methacrylates having anaverage degree of methacrylate substitution of 0.4 to 0.5 are mostsuitable for crosslinking. Such products all have a solubility in waterof more than 25% (w/v) and, in addition, on average at least twopolymerizable groups per cyclodextrin unit.

In addition to the methods described above, fixing of methacrylategroups to cyclodextrin units can also be achieved by reaction ofcyclodextrins or hydroxyalkylcyclodextrins with compounds of type A, thecompounds of type A being used in excess. In this context, the reactionwith glycidyl methacrylate (compound of type A where n=1) isparticularly suitable. ##STR1##

The base-catalysed reaction is preferably carried out inN,N-dimethylformamide at temperatures of 60°-100° C. The catalyst usedcan be, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene. During thereaction the oxirane ring is opened and compounds of type A are bondedvia an ether bond to the cyclodextrin unit. The resulting cyclodextringlyceryl methacrylates or hydroxyalkylcyclodextrin glycerylmethacrylates (for n=1) can be isolated in adequate purity by simpleprecipitation with toluene and subsequent washing with toluene andacetone. Characterization of the products is again effected bydetermining the average degree of substitution (AS) by means of ¹ H NMRspectroscopy (the signal areas of the substituent signals being comparedwith those of the cyclodextrin signals). Reaction products ofcyclodextrins (α, β and γ) or hydroxyalkylcyclodextrins, preferablyhydroxyethylcyclodextrins or hydroxypropylcyclodextrins (having MSvalues of 0.5-1.0), with glycidyl methacrylate, where the average degreeof substitution for glyceryl methacrylate substituents should be between0.3 and 0.9, preferably between 0.4 and 0.5, are particularly suitablefor a polymerization. Such products have a solubility in water of morethan 30% (w/v).

The polymers according to the invention are prepared by inverse, freeradical suspension bead polymerization. In this process theabove-described cyclodextrin derivatives having an average degree ofsubstitution with polymerizable groups of 0.3-0.9, preferably of 0.4 to0.5, are subjected to free radical polymerization in aqueous solution.The concentration of the aqueous monomer solution is between 10 and 50%(w/w). The initiators used are preferably water-soluble peroxidecompounds, such as, for example, potassium peroxodisulfate. Thedispersing agents (outer phase) used can be liquid aromatic or aliphatichydrocarbons, such as toluene, or n-decane. The ratio of outer (organic)to inner (aqueous) phase can be varied between 1:1 and 5:1. Thepolymerization can be carried out at any desired temperature and undernormal pressure or slightly elevated pressure. In a preferredembodiment, emulsifiers are added in order to obtain bead polymershaving a narrow particle size distribution. Suitable emulsifiers arethose customary in suspension polymerization, such as, for example,alkyl sulfates and alkylsulfonates having 8 to 18 C atoms,alkyl-substituted or -ethoxylated phosphoric acid esters or cellulosederivatives. These emulsifiers are preferably used in an amount of 0.5to 5.0% by weight, based on the hydrocarbon phase.

Since on average at least two polymerizable groups per cyclodextrin unitare already present at an AS value of 0.35 (with respect to themethacrylate groups), crosslinked, insoluble products form during thepolymerization described above. As a result of the low AS value of lessthan 0.9, a large number of unsubstituted hydroxyl groups in thecyclodextrin units are still present in the polymer. This leads to ahydrophilic polymer which is swellable in water.

In addition to the homopolymers described above, the invention alsorelates to copolymers of various cyclodextrin derivatives withwater-soluble, ethylenically unsaturated comonomers, such as, forexample, hydroxyethyl acrylate, hydroxyethyl methacrylate or1-vinyl-2-pyrrolidone. They are prepared analogously to the suspensionbead polymerization described, it being possible for the ratio ofpolymerizable cyclodextrin derivative to water-soluble comonomer toreach 10:1 (w/w) to 1:1 (w/w). The bead polymers formed in this processare also exceptionally hydrophilic and swellable in water.

Surprisingly, in the swollen state (in water) the cyclodextrin beadpolymers prepared in this way show distinctly better mechanicalproperties than hydrophilic cyclodextrin polymers readily swellable inwater which are already known (same particle size, same water retentioncapacity, same gel bed volume), for example such as theepichlorohydrin-crosslinked cyclodextrin polymers prepared in accordancewith German Patent Specification DE 29 27 733.

The cyclodextrin bead polymers according to the invention are suitableas column packing material for chromatographic separations of dissolvedsubstances, as catalysts or for the selective removal of hydrophobicsubstances from aqueous solutions.

The following examples serve to illustrate the invention further.

EXAMPLE 1 β-Cyclodextrin methacrylate

160 g of dry β-cyclodextrin are suspended under N₂ blanketing gas in 400ml of dry pyridine, some of the cyclodextrin going into solution. Themixture is heated to 60° C. 60 g of methacrylic anhydride are added atthis temperature and the reaction mixture is stirred for 3 h at 98° C.,virtually all of the cyclodextrin going into solution.

After cooling, the small amount of undissolved solid is filtered off and1200 ml of toluene are added to the filtrate. After stirring for 1 hour,the solid is filtered off, washed with 300 ml of toluene and 2× with, ineach case, 300 ml of n-propanol and dried at 30° C. and a pressure of 50mbar for 20 hours. 179 g of β-cyclodextrin methacrylate (AS=0.4) whichis readily soluble in water (>30% w/v) are obtained. Yield: 96% based onβ-cyclodextrin.

EXAMPLE 2 α-Cyclodextrin methacrylate

75 g of dry α-cyclodextrin are dissolved at 60° C. under N₂ blanketinggas in 100 ml of dry dimethyl sulfoxide. After adding 28 g oftriethylamine and 28.6 g of methacrylic anhydride, the reaction mixtureis stirred for 2 hours at 98° C. After cooling to 20° C., 2000 ml ofacetone are added to the resulting solution and the mixture is stirredfor a further 1 hour. The precipitated α-cyclodextrin methacrylate isfiltered off, washed 2× with, in each case, 200 ml of acetone and driedat 30° C. and a pressure of 50 mbar for 24 hours. 80.6 g ofα-cyclodextrin methacrylate (AS=0.4) which is readily soluble in water(>30% w/v) are obtained. Yield: 92% based on α-cyclodextrin.

EXAMPLE 3 β-Cyclodextrin methacrylate

100 g of dry β-cyclodextrin are dissolved under N₂ blanketing gas in 300ml of dry N,N-dimethylformamide and 37.4 g of triethylamine are added.After heating to 95° C., 38 g of methacrylic anhydride are addedrapidly.

The reaction mixture is then stirred for 3.5 hours at 98° C. After thereaction is complete, the resulting solution is cooled to 20° C. and1500 ml of toluene are added. The precipitated β-cyclodextrinmethacrylate is filtered off, washed once with 300 ml of toluene andtwice with, in each case, 300 ml of n-propanol and then dried at 35° C.and a pressure of 50 mbar for 20 hours. 116 g of β-cyclodextrinmethacrylate (AS=0.4) which is readily soluble in water (>30% w/v) areobtained. Yield: 99% based on β-cyclodextrin.

EXAMPLE 4 β-Cyclodextrin glyceryl methacrylate

75 g of dry β-cyclodextrin and 0.75 g of1,8-dicabicyclo[5.4.0]undec-7-ene are dissolved in 187.5 ml of dryN,N-dimethylformamide. 26.3 g of glycidyl methacrylate are added rapidlyto this solution. The reaction mixture is then stirred for 2.5 h at 98°C. It is then cooled to 25° C. and a small amount of solid is filteredoff. 940 ml of toluene are added to the filtrate. The β-cyclodextringlyceryl methacrylate which precipitates is filtered off and washed with150 ml of toluene and then twice with 250 ml of acetone.

After drying for 18 hours at 35° C. and a pressure of 50 mbar, 96 g ofβ-cyclodextrin glyceryl methacrylate (AS=0.4) which is readily solublein water (>30% w/v) are obtained.

Yield: 95% based on β-cyclodextrin.

EXAMPLE 5 Hydroxypropyl-β-cyclodextrin glyceryl methacrylate

Hydroxypropyl-β-cyclodextrin glyceryl methacrylate is prepared asdescribed in Example 4, 91 g of hydroxypropyl-β-cyclodextrin (MS=0.6)being employed in place of β-cyclodextrin.

112 g of hydroxypropyl-β-cyclodextrin glyceryl methacrylate(MS_(hydroxypropyl) =0.6; AS_(glyceryl) methacrylate =0.4) which is,readily soluble in water (>30% w/v) are obtained.

Yield: 95% based on hydroxypropyl-β-cyclodextrin (MS=0.6).

EXAMPLE 6 Hydroxypropyl-β-cyclodextrin methacrylate

Hydroxypropyl-β-cyclodextrin methacrylate is prepared as described inExample 3, 132 g of hydroxypropyl-β-cyclodextrin (MS=0.9) being employedin place of β-cyclodextrin.

140 g of hydroxypropyl-β-cyclodextrin methacrylate (MS_(hydroxypropyl)=0.9; AS_(methacrylate) =0.4) which is readily soluble in water (>30%w/v) are obtained. Yield: 94% based on hydroxypropyl-β-cyclodextrin(MS=0.9).

EXAMPLE 7 γ-Cyclodextrin methacrylate

γ-Cyclodextrin methacrylate is prepared as described in Example 3, 100 gof γ-cyclodextrin being employed in place of β-cyclodextrin. 99 g ofγ-cyclodextrin methacrylate (AS=0.4) which is readily soluble in water(>30% w/v) are obtained.

Yield: 85% based on γ-cyclodextrin.

EXAMPLE 8 Polymerization of β-cyclodextrin glyceryl methacrylate

4.05 g of the emulsifier "Gafac RM 510" from GAF (Deutschland) GmbH,5020 Frechen (complex phosphoric acid ester) are added to 405 ml ofn-decane under N₂ blanketing gas in a cylindrical 1 l glass vesselprovided with an impeller stirrer and a heating jacket and the mixtureis stirred at 70° C. and at a stirrer speed of 750 rpm.

45 g of β-cyclodextrin glyceryl methacrylate (AS=0.4) are dissolved in90 g of deionized water at 25° C. and 23 g of 5% strength (w/v) aqueouspotassium peroxodisulfate solution are added. This solution is pouredinto the n-decane phase with stirring. The resulting emulsion is stirredfor 2.5 h at 75° C. and 750 rpm, a polymer in bead form being formed.

The resulting suspension is cooled to 25° C. and the polymer solid isfiltered off and washed with 100 ml of n-decane, 150 ml of ethanol,twice with, in each case, 150 ml of water and finally again with 150 mlof ethanol.

42 g (yield: 93%) of polymer are obtained in the form of uniform beadshaving an average particle size of 15 μm. In water, the polymer shows aswelling of 1.8 g/g and a gel bed volume of 4.2 ml/g. In order todetermine the stability of the resulting cyclodextrin gel to pressure,the flow-through rate of water through a column packed with the gel(packed height: 30 cm; °: 2.5 cm) was measured. The flow-through rate is35 ml/min under a pressure of 10 bar.

EXAMPLE 9 Polymerization of hydroxypropyl-β-cyclodextrin methacrylate

The polymerization is carried out as described in Example 8, 45 g ofhydroxypropyl-β-cyclodextrin methacrylate (MS_(hydroxypropyl) =0.9;AS_(methacrylate) =0.4) being employed in place of β-cyclodextringlyceryl methacrylate.

44 g (yield: 98%) of polymer in bead form with an average particlediameter of 30 μm, a swelling of 2.1 g/g and a gel bed volume of 5.2ml/g are obtained. The flow-through rate is 40 ml/min under a pressureof 10 bar.

EXAMPLE 10 Copolymerization of β-cyclodextrin methacrylate withacrylamide

The polymerization is carried out as described in Example 8, the monomersolution used being a solution of 21 g of acrylamide and 60 g ofβ-cyclodextrin methacrylate (AS=0.4) in 87 g of deionized water, whichsolution is used for the polymerization after the addition of 23 g of 5%strength (w/v) potassium peroxodisulfate solution in n-decane asdispersing agent. 74 g (yield: 91%) of polymer in bead form with anaverage particle diameter of 50 μm and a swelling of 1.8 g/g and a gelbed volume of 5.5 ml/g are obtained. The flow-through rate is 90 ml/minunder a pressure of 10 bar.

EXAMPLE 11 Copolymerization of β-cyclodextrin methacrylate with1-vinyl-2-pyrrolidone

In the apparatus described in Example 8, 405 ml of n-decane and 4.05 gof the emulsifier "Cremophor WO 7" from BASF (hydrogenated castor oilwhich has additionally been reacted with ethylene oxide) are prepared asouter phase for an inverse suspension polymerization at 75° C. Under anitrogen atmosphere, a solution of 60 g of β-cyclodextrin methacrylate(AS=0.4) and 16 g of 1-vinyl-2-pyrrolidone in 80 g of deionized water isprepared and 23 g of 5% strength (w/v) aqueous potassium peroxodisulfatesolution are added. Immediately thereafter this mixture is emulsified inthe n-decane phase. The resulting emulsion is stirred for 2.5 h at 75°C. and 750 rpm, a polymer in bead form being formed. Working up iscarried out in accordance with the method described in Example 8.

71 g (yield 93%) of a polymer in bead form which has an average particlediameter of 35 μm, a swelling of 1.9 g/g and a gel bed volume of 5.2ml/g are obtained. The flow-through rate is 55 ml/min under a pressureof 10 bar.

EXAMPLE 12 Copolymerization of α-cyclodextrin methacrylate withhydroxyethyl methacrylate

In the apparatus described in Example 8, 450 ml of toluene and 4.05 g ofthe emulsifier "Ethocel 22 cps" from Janssen Chimica (ethylcellulose)are prepared under N₂ blanketing gas, at 75° C., as outer phase for aninverse suspension polymerization. A solution of 60 g of α-cyclodextrinmethacrylate and 21 g of hydroxyethyl methacrylate in 88 g of deionizedwater, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution have been added, is emulsified in this phase.The resulting emulsion is stirred for 2.5 h at 75° C. and 750 rpm, apolymer in bead form being formed. Working up is carried out inaccordance with the method described in Example 8.

72 g (yield: 89%) of polymer in bead form which has an average particlediameter of 50 μm, a swelling of 1.7 g/g and a gel bed volume of 4.8ml/g are obtained. The flow-through rate is 150 ml/min under a pressureof 10 bar.

EXAMPLE 13 Copolymerization of β-cyclodextrin methacrylate withhydroxyethyl acrylate

The polymerization is carried out as described in Example 8, but themonomer solution used is a solution of 60 g of β-cyclodextrinmethacrylate (AS=0.4) and 16 g of hyroxy(sic)ethyl acrylate in 80.5 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution have been added.

83 g (yield: 96.5%) of polymer in bead form which has an averageparticle diameter of 25 μm, a swelling of 1.6 g/g and a gel bed volumeof 4.9 ml/g are obtained. The flow-through rate is 40 ml/min under apressure of 10 bar.

EXAMPLE 14 Copolymerization of β-cyclodextrin methacrylate withhydroxyethyl methacrylate

The polymerization is carried out as described in Example 8, but themonomer solution used is a solution of 62 g of β-cyclodextrinmethacrylate (AS=0.4) and 31 g of hydroxyethyl methacrylate in 70 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution has been added. 88 g (yield: 95%) of polymer inbead form which has an average particle diameter of 75 μm, a swelling of1.2 g/g and a gel bed volume of 3.7 ml/g are obtained. The flow-throughrate is 250 ml/min under a pressure of 10 bar.

EXAMPLE 15 Copolymerization of hydroxypropyl-β-cyclodextrin methacrylatewith hydroxyethyl methacrylate

The polymerization is carried out as described in Example 8, but themonomer solution used is a solution of 62 g ofhydroxypropyl-β-cyclodextrin methacrylate (MS_(hydroxypropyl) =0.9;AS_(methacrylate) =0.4) and 31 g of hydroxyethyl methacrylate in 70 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate have been added.

85 g (yield: 91%) of polymer in bead form which has an average particlediameter of 70 μm, a swelling of 1.3 g/g and a gel bed volume of 4.0ml/g are obtained. The flow-through rate is 190 ml/min under a pressureof 10 bar.

EXAMPLE 16 Copolymerization of β-cyclodextrin glyceryl methacrylate withhydroxyethyl methacrylate

The polymerization is carried out as described in Example 8, but themonomer solution used is a solution of 37 g of β-cyclodextrin glycerylmethacrylate (AS=0.4) and 37 g of hydroxyethyl methacrylate in 90 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution have been added.

70 g (yield: 95%) of polymer in gel form which has an average particlediameter of 40 μm, a swelling of 1.2 g/g and a gel bed volume of 3.8ml/g are obtained. The flow-through rate is 200 ml/min under a pressureof 10 bar.

EXAMPLE 17 Copolymerization of β-cyclodextrin glyceryl methacrylate withhydroxyethyl acrylate

The polymerization is carried out as described in Example 17, but themonomer solution used is a solution of 45 g of β-cyclodextrin glycerylmethacrylate (AS=0.4) and 45 g of hydroxyethyl acrylate in 90 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution have been added.

83 g (yield: 92%) of polymer in bead form which has an average particlediameter of 40 μm, a swelling of 2.0 g/g and a gel bed volume of 6.0ml/g are obtained. The flow-through rate is 40 ml/min under a pressureof 10 bar.

EXAMPLE 18 Copolymerization of β-cyclodextrin methacrylate withβ-cyclodextrin glyceryl methacrylate

The polymerization is carried out as described in Example 17, but themonomer solution used is 40 g of β-cyclodextrin methacrylate (AS=0.4)and 20 g of β-cyclodextrin glyceryl methacrylate (AS=0.4) in 90 g ofdeionized water, to which 23 g of 5% strength (w/v) aqueous potassiumperoxodisulfate solution have been added.

53 g (yield: 89%) of a polymer in bead form which has an averageparticle diameter of 50 μm, a swelling of 1.3 g/g and a gel bed volumeof 3.4 ml/g are obtained. The flow-through rate is 30 ml/min under apressure of 10 bar.

EXAMPLE 19 Polymer composed of β-cyclodextrin methacrylate,β-cyclodextrin glyceryl methacrylate and 1-vinyl-2-pyrrolidone

The polymerization is carried out as described in Example 17, but themonomer solution used is a solution of 36 g of β-cyclodextrinmethacrylate (AS=0.4), 36 g of β-cyclodextrin glyceryl methacrylate and18 g of 1-vinyl-2-pyrrolidone in 90 g of deionized water, to which 23 gof 5% strength (w/v) aqueous potassium peroxodisulfate solution havebeen added.

83 g (yield: 92%) of a polymer in bead form which has an averageparticle diameter of 50 μm, a swelling of 1.9 g/g and a gel bed volumeof 4.0 ml/g are obtained. The flow-through rate is 80 ml/min under apressure of 10 bar.

EXAMPLE 20 Polymer composed of β-cyclodextrin methacrylate,β-cyclodextrin glyceryl methacrylate and hydroxyethyl methacrylate

The polymerization is carried out as described in Example 15, but themonomer solution used is a solution of 22.5 g of β-cyclodextrinmethacrylate (AS=0.4), 22.5 g of β-cyclodextrin glyceryl methacrylate(AS=0.4) and 45 g of hydroxyethyl methacrylate in 90 g of deionizedwater, to which 23 g of 5% strength (w/v) potassium peroxodisulfatesolution have been added.

83 g (yield: 92%) of a polymer in bead form which has an averageparticle diameter of 50 μm, a swelling of 1.2 g/g and a gel bed volumeof 4.9 ml/g are obtained. The flow-through rate is 150 ml/min under apressure of 10 bar.

To determine the mechanical properties, the flow rate of water through acolumn packed with cyclodextrin polymer was measured as a function ofthe pressure. The diameter of the column was 2.5 cm and the packedheight of the cyclodextrin polymer pre-swollen in water was 30 cm.

In these pressure tests it was found that, for example, the cyclodextrinpolymers described by J. Szejtli in DE 29 27 733, which already hadimproved mechanical properties compared with previously known similarpolymers, already have their maximum flow-through rate at a pressure ofless than 3 bar. There is no further increase in this flow-through ratewith further increasing pressure. The cyclodextrin polymers according tothe invention, on the other hand, show a continuous rise in theflow-through rate with increasing pressure up to at least 10 bar. Undera pressure of 10 bar, the absolute flow-through rates are, moreover,distinctly higher than in the case of the polymer prepared in accordancewith DE 29 27 733. In these tests, bead polymers of the same diameter,and also the same water retention capacity (swelling) and gel bedvolume, were always compared with one another.

FIG. 1

Flow-through rate for an epichlorohydrin-crosslinked β-cyclodextrinpolymer prepared in accordance with DE 29 27 733 (swelling 1.5 g/g; gelbed volume 3.2 ml/g; average particle size 150 μm)

FIG. 2

Flow-through rate for the copolymer according to Example 14 (swelling1.2 g/g; gel bed volume 3.7 ml/g; average particle size 75 μm)

We claim:
 1. A water-insoluble hydrophilic cyclodextrin polymer selectedfrom the group consisting ofwith the exception of a homopolymer ofmethacrylate cyclodextrin; a copolymer of a methacrylate substitutedcyclodextrin; a homopolymer of glyceryl methacrylate substitutedcyclodextrin; a copolymer of glyceryl methacrylate substitutedcyclodextrins; a homopolymer of methacrylate hydroxyalkyl cyclodextrincontaining C₂ to C₄ hydroxyalkyl units; a copolymer of methacrylatehydroxyalkyl cyclodextrin containing C₂ to C₄ hydroxyalkyl units; ahomopolymer of glyceryl methacrylate hydroxyalkyl cyclodextrincontaining C₂ to C₄ hydroxyalkyl units; a copolymer of glycerylmethacrylate hydroxyalkyl cyclodextrin containing C₂ to C₄ hydroxyalkylunits; each of said above-noted methacrylate containing polymers havingan AS value between 0.3 and 0.9; and a copolymer of the said substitutedcyclodextrin derivatives with a water-soluble ethylenically unsaturatedcomonomer selected from the group consisting of acrylamide,1-vinyl-2-pyrrolidone, hydroxyethyl acrylate and hydroxyethylmethacrylate.
 2. The cyclodextrin polymer as claimed in claim 1,whereinthe cyclodextrin content is more than 30% by weight, based on the totalpolymer weight.
 3. A process for the preparation of a water-insolublehydrophilic cyclodextrin polymer consisting essentially of the stepsofproviding monomers capable of preparing said cyclodextrin polymerselected from the group consisting of with the exception of ahomopolymer of methacrylate cyclodextrin; a copolymer of a methacrylatesubstituted cyclodextrin; a homopolymer of glyceryl methacrylatesubstituted cyclodextrin; a copolymer of glyceryl methacrylatesubstituted cyclodextrins; a homopolymer of methacrylate hydroxyalkylcyclodextrin containing C₂ to C₄ hydroxyalkyl units; a copolymer ofmethacrylate hydroxyalkyl cyclodextrin containing C₂ to C₄ hydroxyalkylunits; a homopolymer of glyceryl methacrylate hydroxyalkyl cyclodextrincontaining C₂ to C₄ hydroxyalkyl units; a copolymer of glycerylmethacrylate hydroxyalkyl cyclodextrin containing C₂ to C₄ hydroxyalkylunits; each of said above-noted methacrylate containing polymers havingan AS value between 0.3 and 0.9; a copolymer of the said substitutedcyclodextrin derivatives with a water-soluble ethylenically unsaturatedcomonomer selected from the group consisting of acrylamide,1-vinyl-2-pyrrolidone, hydroxyethyl acrylate and hydroxyethylmethacrylate; polymerizing said monomers by free radical suspensionpolymerization under normal pressure in a two-phase medium comprising anaqueous phase and an organic hydrocarbon phase in a weight ratio of 1:1to 1:5; and using a monomer concentration in the aqueous phase of 10% to50% by weight, based on the total weight of the aqueous phase.
 4. Theprocess as claimed in claim 3, comprisingcarrying out saidpolymerization in the presence of water-soluble ethylenicallyunsaturated comonomers, with the ratio of cyclodextrin orhydroxyalkylcyclodextrin derivatives or the mixtures thereof to saidwater-soluble comonomer being from 10:1 (w/w) to 1:1 (w/w).